Escitalopram

Additional information

Escitalopram is the (S)-enantiomer of citalopram.Depression is almost twice as common in women as in men [1]. Women have an earlier age of onset and increased duration of depressive episodes. Differences in neurobiology [2, 3], hormones, inflammatory markers, diagnostic tools, or health seeking behavior [4, 5] may be of importance.  Although depression is more prevalent in women, most preclinical studies on depression have used  male animals [2].

Women are two to three times more likely to suffer from an anxiety disorder [1]. Sex differences in symptomatology and comorbidity  may be due to genetic, hormonal, neurodevelopmental, environmental, and neurobiological factors [6].

Pharmacokinetics and dosing

There are contradictory results from pharmacokinetic studies of citalopram (CIT) and escitalopram (S-CIT). No sex differences in the pharmacokinetics of the metabolites desmethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) have been shown.

For citalopram, AUC was 1.5–2 times higher in women than in men in three pharmacokinetic studies (in total 32 patients) conducted by the original manufacturer. However, in five other pharmacokinetic studies (in total 114 patients) no sex differences were seen. Clinical studies (237 men, 338 women) showed no differences in citalopram concentration between men and women  [7, 8]. Also in healthy volunteers, no differences in pharmacokinetics between men and women after a single dose of 20 mg citalopram were found [9].However, in a sample of patients taking citalopram (216 men, 300 women), the dose corrected citalopram concentration was found to be higher in men than women in the higher dose range, 70-200 mg citalopram daily. No difference in citalopram concentration was observed for the lower dose, 10-60 mg daily [10] .In a TDM study (247 men, 502 women), women had higher dose corrected concentrations for citalopram and DCIT and also lower citalopram clearance than men (21.7 vs. 25.5 L/h). No differences were observed in DCIT to citalopram ratio [11]. Similar to this, another TDM study observed 25% higher citalopram and 9% higher escitalopram concentrations in women than men after receiving 20 mg citalopram daily or 10 mg escitalopram daily (1344 men, 2456 women) [12]. Contrary to these findings, another TDM study in psychiatric patients (57 men, 112 women) found no significant sex differences in pharmacokinetics for citalopram and the metabolite DCIT after a mean daily dose of 40 mg [13] .

For escitalopram, the concentrations of escitalopram and the metabolites DCIT and DDCIT were analyzed in patients (50 men, 105 women) with a median daily dose of 20 mg daily. No differences in dose-normalized concentrations were found. However, the DCIT/escitalopram ratio was higher in women (0.64 vs. 0.50) as well as the concentration-over-dose for DCIT variance (45% vs. 35%) [14].

Despite these findings, the clinical studies have shown effect with similar doses in men and women and no dose adjustment based on patient’s sex has been suggested  [7, 8].

Effects

The original manufacturers of citalopram and escitalopram report no relationship between treatment outcome and patient’s sex . However, results vary between clinical studies. The large STAR*D study of major depression (1043 men, 1833 women, age 18-75 years), showed that women had better self-rated response and remission than men after treatment with citalopram for 12–14 weeks. Similar proportions of men and women completed treatment for 8 weeks or more [15]. However, another study in patients with major depression (96 men, 196 women) showed no sex differences in response or dropout rates after 5 weeks of treatment with citalopram dose of 40 mg daily [16] .

Menopausal women had a worse SSRI treatment response compared to non-menopausal women in a clinical study of  different SSRIs including citalopram (59 men, 95 menopausal women, 147 non-menopausal women). In contrast, no differences were shown between men and women [17].

For use of citalopram in alcohol dependence, a placebo-controlled study showed men to have a better outcome. After 12 weeks of treatment of citalopram 40 mg daily in patients with alcohol dependence (16 men, 15 women), the men reduced their average drinks per day by 44% compared to 27% for women [18]. However, citalopram and escitalopram are not approved on this indication in Sweden.

Adverse effects

A general alert has been issued about older patients, especially older women, and the risk of QT-prolongation when treated with citalopram doses above 20 mg daily [19, 20]. It is well described in cardiology reports that treatment with citalopram and escitalopram induces QT-prolongation and increases the risk of lethal ventricular tachycardia type Torsade de Pointes to a greater extent in women, especially with hypokalemia and/or heart diseases. Also, elderly women are at higher risk of citalopram-induced hyponatremia [21, 22].

The STAR*D study reported no sex differences in overall serious adverse effects or psychiatric serious adverse effects [15].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).